This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall objective of the proposed studies is to establish ethanol magnetic resonance spectroscopy (MRS) as a translational measure of tolerance. In a series of in vivo MRS experiments following intravenous ethanol administration, we have observed that the size of the ethanol MRS signal is a non-linear function of ethanol concentration. We have developed a framework to interpret this finding in terms of the concentration and affinity of a saturable ethanol binding site (or collection of binding sites) within the brain. Our data corroborate early spectroscopic results from human investigations, and provide an opportunity to extend these earlier findings by incorporating modern analysis strategies and a previously unrecognized biophysical model of ethanol binding interactions with macromolecular constituents. Within this context, we will provide the first direct comparison between ethanol MRS measures of tolerance, well-established behavioral measurements of acute tolerance, and the development of acquired tolerance. Each of these measurements will be interpreted in terms of the propensity to self-administer excessive quantities of ethanol, which will also be directly measured in our non-human primate study. First, we will test the hypothesis that a high degree of innate tolerance to the intoxicating effects of ethanol is detectable through an endophenotype of increased BEC-corrected ethanol MRS signal intensity. Second, we will test the hypothesis that BEC-corrected ethanol MRS signal intensity increases as an individual transitions from an ethanol-na[unreadable]ve state to a state of excessive ethanol self-administration.